Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease, such as arteriosclerosis. Bile acid sequestrants have been used to treat this condition; they seem to be moderately effective but they must be consumed in large quantities, i.e. several grams at a time, and they are not very palatable.
MEVACOR.RTM. (lovastatin) and ZOCOR.RTM. (simvastatin), now commercially available, are members of a group of very active antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase.
Squalene synthase is the enzyme involved in the first committed step of the de novo cholesterol biosynthetic pathway. This enzyme catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate to form squalene. The inhibition of this committed step to cholesterol should leave unhindered biosynthetic pathways to ubiquinone, dolichol, and isopentyl t-RNA.
Previous efforts at inhibiting squalene synthase have been employed pyrophosphate or Pyrophosphate analog containing compounds such as those described in P. Ortiz de Montellano et al. J. Med. Chem. 20, 243 (1977) and E. J. Corey and R. Volante, J. Am. Chem. Soc., 98, 1291 (1976). S. Biller (U.S. Pat. No. (4,871,721) describes isoprenoid (phosphinylmethyl) phosphonates as inhibitors of squalene synthase.
Recently certain nonphosphorous containing inhibitors of squalene synthase have been isolated as natural products. For example, U.S. Pat. No. 5,055,487 issued Oct. 8, 1991 describes compounds of structural formula (III): ##STR2## and their use as cholesterol lowering agents and antifungal agents. In particular, this patent discloses preparation of the compound wherein Z.sub.1, Z.sub.2 and Z.sub.3 are each hydrogen (i.e., compound II) by aerobic fermentation procedures employing fungal cultures MF5447 (ATCC 20985) and MF5466 (ATCC 20989). MF5447 is that of a coprophilous fungus, Sporormiella intermedia, isolated from cottontail rabbit dung (Arizona). MF5466 is that of coprophilous fungus, a bitunicate ascomycete, isolated from big horn sheep dung (Tuscon, Ariz.). A need still remains for a more effective squalene synthase inhibitor, i.e., one that provides a greater antihypercholesterolemic effect and exhibits a good safety profile.
The present invention is directed to biotransformed analogs of the above-noted natural products.